## Doctoral Dissertations

Spring 1996

Dissertation

Biochemistry

#### Degree Name

Doctor of Philosophy

The identification in invertebrates of genes homologous to human disease genes provides the possibility to broaden the spectrum of model organisms to include experimental invertebrates. The goal of this study is to test the possibility of using Caenorhabditis elegans as an animal model for the inherited human heart disorder familial hypertrophic cardiomyopathy. In 10-30% of the affected families that have been studied, this disease is caused by mutations in the $\beta$-cardiac myosin heavy chain (MHC) gene. The most common of these mutations results in the replacement of an evolutionarily conserved arginine residue (R403) with glutamine (R403Q). While this information has been useful for diagnostic purposes, it has revealed little about the molecular basis of FHC. How do these mutations affect cardiac muscle structure and contractility and result in cardiac hypertrophy? Using a novel gene replacement approach, I introduced the corresponding mutation (R404Q) into the unc-54 gene, which encodes the predominant myosin heavy chain in the body-wall muscle of C. elegans. The phenotype of the unc-54(R404Q) mutant is essentially wild-type. Detailed characterization of the R404Q mutant has yielded information which highlights differences between nematode and vertebrate striated muscle which may be key factors in the pathogenesis of the disease.